Strain-specific effects of rosiglitazone on bone mass, body composition, and serum insulin-like growth factor-I.
Activation of peroxisome proliferator activated receptor-gamma (PPARG) is required for the differentiation of marrow mesenchymal stem cell into adipocytes and is associated with the development of age-related marrow adiposity in mice. Thiazolidinediones are agonists for PPARG and have a heterogeneous effect on bone mineral density (BMD). We postulated that genetic determinants influence the skeletal response to thiazolidinediones. We examined the effects of rosiglitazone (3 mg/kg . d for 8 wk) on BMD, body composition, and serum IGF-I in adult female mice from four inbred strains. C3H/HeJ mice showed the most significant response to treatment, exhibiting decreased femoral and vertebral BMD, reduced distal femoral bone volume fraction and a decrease in serum IGF-I. In DBA/2J, there were no changes in femoral BMD or bone volume fraction, but there was a decrease in vertebral BMD. C57BL/6J mice showed increases in marrow adiposity, without associated changes in trabecular bone volume; the skeletal effects from rosiglitazone in A/J mice were minimal. No association between trabecular bone volume and marrow adiposity was found. The effect of rosiglitazone on gene expression in the femur was then examined in the C3H/HeJ and C57BL/6J strains by microarray. Increased gene expression was observed in the PPARG signaling pathway and fatty acid metabolism in both C3H/HeJ and C57BL/6J, but a significant down-regulation of genes associated with cell cycle was noted only in the C3H/HeJ strain. The divergent skeletal responses to rosiglitazone in this study suggest the existence of a strong genetic background effect.
Ackert-Bicknell
Cheryl L
CL
The Jackson Laboratory, Bar Harbor, Maine 04609, USA.
Shockley
Keith R
KR
Horton
Lindsay G
LG
Lecka-Czernik
Beata
B
Churchill
Gary A
GA
Rosen
Clifford J
CJ
D050154:Adiposity / Q000187:drug effects; D000818:Animals; D001823:Body Composition / Q000187:drug effects*; D015519:Bone Density / Q000187:drug effects; D001842:Bone and Bones / Q000033:anatomy & histology / Q000187:drug effects*; D005260:Female; D005269:Femur / Q000033:anatomy & histology / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000032:analysis / Q000187:drug effects*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008815:Mice, Inbred Strains / Q000235:genetics; D009929:Organ Size / Q000187:drug effects; D000077154:Rosiglitazone; D013045:Species Specificity; D045162:Thiazolidinediones / Q000494:pharmacology*
D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D007334:Insulin-Like Growth Factor I